ID3-depleted human induced pluripotent stem cell–derived neural stem/progenitor cells promote neurorepair

Human induced pluripotent stem cell-derived neural stem/progenitor cells are used in cell-replacement and regenerative therapeutic strategies after traumatic central nervous system injury. Traumatic injury alters the host microenvironment, which in turn affects the functionality of transplanted human neural stem/ progenitor cells and potentially limits their benefits for neurorepair. However, the underlying mechanisms through which the host environment alters the fate and functionality of transplanted human neural stem/progenitor cells remain poorly understood. Here, we showed that massive deposition of blood-derived fibrinogen in a mouse model of spinal cord injury contributed to an altered lesion environment. Fibrinogen promoted human neural stem/progenitor cell differentiation into reactive astrocytes by activating the BMP receptor signaling pathway and inducing of the transcriptional regulator inhibitor of DNA binding 3. ID3 -depleted human neural stem/progenitor cells, generated by CRISPR/Cas9-mediated genome editing, reduced astrocyte formation in response to astrogenic stimuli. Instead, ID3 -depleted human neural stem/progenitor cells had a bipolar, immature glial progenitor cell phenotype. These modified cells secreted extracellular vesicles with a distinct miRNA profile that enhanced neurite outgrowth. We conclude that targeting inhibitor of DNA binding 3 in human neural stem/progenitor cells can beneficially modulate their functionality and cell fate in the injured central nervous system toward glial progenitor cells, potentially enhancing their capacity to promote central nervous system repair.